Heparin-azithromycin microparticles inhibit SARS-CoV-2 and bacterial lung infections

Anaya, Bryan J and D'Angelo, Davide and Bettini, Ruggero and Molina, Gracia and Sanz, Amadeo and Dea-Ayuela, Maria Auxiliadora and Galiana, Carolina and Rodriguez, Carmina and Tirado, Diego F and Lalatsa, Katerina and Gonzalez-Burgos, Elena and Serrano, Dolores R. (2024) Heparin-azithromycin microparticles inhibit SARS-CoV-2 and bacterial lung infections. Carbohydrate Polymers. 122930. ISSN 0144-8617 (https://doi.org/10.1016/j.carbpol.2024.122930)

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Abstract

Pulmonary infections are a leading cause of morbidity and mortality worldwide, a situation exacerbated by the COVID-19. Azithromycin (AZM) is used orally to treat pulmonary infections due to its ability to accumulate in lung tissues and immune cells after oral administration. Sulfated polysaccharides, such as heparin, are known to inhibit SARS-CoV-2 entry. This study presents a novel approach focused on developing a dry powder inhaler of AZM-loaded microparticles composed of either heparin or its derivatives. The microparticle formulations exhibited potent antiviral activity against SARS-CoV-2 (IC50 ≤ 95 nM) while retaining superior antibacterial efficacy against Streptococcus pneumoniae and Pseudomonas aeruginosa compared to free AZM (MIC ≤ 15 μg/mL). Importantly, at bactericidal concentrations, no cytotoxic effects were observed on mammalian cells, including Calu-3 cells and red blood cells. The formulations demonstrated effective alveolar aerodynamic deposition (MMAD ranging from 1 μm to 3 μm) with a Fine Particle Fraction below 5 µm close to 50 %. Adopting a conservative estimate of 20 mL for the pulmonary epithelial lining fluid volume in healthy adults, efficacious local concentrations of sulfated polysaccharides and AZM would be delivered to the lung using this multifaceted strategy which holds promise for the treatment of bacterial pulmonary infections associated with COVID-19.

ORCID iDs

Anaya, Bryan J, D'Angelo, Davide, Bettini, Ruggero, Molina, Gracia, Sanz, Amadeo, Dea-Ayuela, Maria Auxiliadora, Galiana, Carolina, Rodriguez, Carmina, Tirado, Diego F, Lalatsa, Katerina ORCID logoORCID: https://orcid.org/0000-0003-4791-7468, Gonzalez-Burgos, Elena and Serrano, Dolores R.;
CORE (COnnecting REpositories)